The present invention relates to novel substituted 1,3-oxathiolane and substituted-1,3-dioxolane cyclic compounds having pharmacological activity, to processes for and intermediates of use in their preparation, to pharmaceutical compositions containing them, and to the use of these compounds in the antiviral treatment of mammals.
Retroviral infections are a serious cause of disease, most notably, the acquired immunodeficiency syndrome (AIDS). The human immunodeficiency virus (HIV) has been recognized as the etiologic agent of AIDS, and compounds having an inhibitory effect against HIV multiplication have been actively sought.
Mitsuya et al., xe2x80x9c3xe2x80x2-Azido-3xe2x80x2-deoxythymidine (BW A509U): An antiviral agent that inhibits the infectivity and cytopathic effect of human T-lympho-tropic virus type III/lymphadenopathy-associated virus in vitroxe2x80x9d, Proc. Natl. Acad. Sci. U.S.A., 82, pp. 7096-7100 (1985), refers to a compound of formula (A) (3xe2x80x2-azido-2xe2x80x2,3xe2x80x2-dideoxythymidine), commonly referred to as AZT. This compound is said to be useful in providing some protection for AIDS carriers against the cytopathogenic effect of immunodeficiency virus (HIV). 
Mitsuya et al., xe2x80x9cInhibition of the in vitro infectivity and cytopathic effect of human T-lympho-trophic virus type III/lymphadenopathy-associated virus (HTLV-III/LAV) by 2xe2x80x23xe2x80x2-dideoxynucleosidesxe2x80x9d, Proc. Natl. Acad. Sci. U.S.A., 86, pp. 1911-15 (1986), have also referred to a group of 2xe2x80x2,3xe2x80x2-dideoxynucleosides shown in formula (B) which are said to possess protective activity against HIV-induced cytopathogenicity. 
Balzarini et al., xe2x80x9cPotent and selective anti-HTLV-III/LAV activity of 2xe2x80x2,3xe2x80x2-dideoxycytidinene, the 2xe2x80x2,3xe2x80x2-unsaturated derivative of 2xe2x80x2,3xe2x80x2-dideoxycytidinexe2x80x9d, Biochem. Biophys. Res. Comm., 140, pp. 735-42 (1986), refer to an unsaturated analogue of these nucleosidesxe2x80x942xe2x80x2,3xe2x80x2-dideoxycytidine, shown in formula (C)xe2x80x94as being characterized by antiretroviral activity. 
Baba et al., xe2x80x9cBoth 2xe2x80x2,3xe2x80x2-dideoxythymidine and its 2xe2x80x2,3xe2x80x2-unsaturated derivative (2xe2x80x2,3xe2x80x2-dideoxythymidine) are potent and selective inhibitors of human immunodeficiency virus replication in vitroxe2x80x9d, Biochem. Biophys. Res. Comm., 142, pp. 128-34 (1987), refer to the 2xe2x80x2,3xe2x80x2-unsaturated analogue shown in formula (D) of 2xe2x80x2,3xe2x80x2-dideoxythymidine. This analogue is purported to be a potent selective inhibitor of HIV replication. 
Analogues of AZT known as 3xe2x80x2-azido-2xe2x80x2,3xe2x80x2-dideoxyuridine shown in formula (E), where Y is bromine or iodine, have been said to have an inhibitory activity against Moloney murine leukemia in T. S. Lin et al., xe2x80x9cSynthesis and antiviral activity of various 3xe2x80x2-azido,3xe2x80x2 amino,2xe2x80x2,3xe2x80x2-unsaturated and 2xe2x80x2,3xe2x80x2-dideoxy analogues of pyrimidine, deoxyribonucleosides against retrovirusesxe2x80x9d, J. Med. Chem., 30, pp. 440-41 (1987). 
Finally, the 3xe2x80x2-fluoro analogues of 2xe2x80x2,3xe2x80x2-dideoxythymidine shown in formula (F) and of 2xe2x80x2,3xe2x80x2-dideoxythymidine shown in formula (G) are referred to in Herdewijn et al., xe2x80x9c3xe2x80x2-Substituted 2xe2x80x2,3xe2x80x2-dideoxynucleoside analogues as potential anti-HIV(HTLV-III/LAV) agentsxe2x80x9d, J. Med. Chem., 30, pp. 1270-78 (1987), as having potent antiretroviral activity. 
The most potent anti-HIV compounds thus far reported are 2xe2x80x2,3xe2x80x2-dideoxynucleosides, more particularly, 2xe2x80x2,3xe2x80x2-dideoxy cytidine (ddCyd) and 3xe2x80x2-azido-2xe2x80x2,3xe2x80x2-dideoxythymidine (AzddThd or AZT). These compounds are also active against other kinds of retroviruses such as the Moloney murine leukemia virus. Because of the increasing incidence and the life-threatening characteristics of AIDS, efforts are being expended to discover and develop new non-toxic and potent inhibitors of HIV and blockers of its infectivity. It is therefore an object of the present invention to provide effective anti-HIV compounds of low toxicity and a synthesis of such new compounds that is readily feasible.
A structurally distinct class of compounds known as 2-substituted-5-substituted-1,3-oxathiolanes and 2-substituted-4-substituted-1,3-dioxolanes has now been discovered and found to have antiretroviral activity. In particular, these compounds have been found to act as non-toxic inhibitors of the replication of HIV-1 in T-lymphocytes over prolonged periods of time.
There are accordingly provided in a first aspect of this invention compounds of formula (I) 
wherein R1 is hydrogen or an acyl radical from 1 to 16 carbon atoms, preferably a benzoyl or a benzoyl substituted in any position by at least one halogen (bromine, chlorine, fluorine or iodine), C1-6 alkyl, C1-6 alkoxy, nitro or trifluoromethyl groups;
R2 is a purine or pyrimidine base or an analogue or derivative thereof;
Z is O, S, Sxe2x95x90O or SO2; and
R1 can be, for example, acetyl, hexanoyl, or aroyl.
The art that the compounds of formula (I) contain at least two chiral centers (shown as * in formula (I)) and thus exist in the form of two pairs of optical isomers (i.e., enantiomers) and mixtures thereof including racemic mixtures. Thus the compounds of formula (I) may be either cis isomers, as represented by formula (II), or trans isomers, as represented by formula (III), or mixtures thereof. Each of the cis and trans isomers can exist as one of two enantiomers or as mixtures thereof including racemic mixtures. All such isomers and mixtures thereof including racemic mixtures are included within the scope of the invention. 
The compounds of formula (I) are preferably in the form of their cis isomers.
It will also be appreciated that when Z is Sxe2x95x90O the compounds exist in two additional isomeric forms as shown in formulas (IIa) and (IIb) which differ in the configuration of the oxide oxygen atom relative to the 2,5-substituents. The compounds of the invention additionally embrace such isomers and mixtures thereof. 
The purine or pyrimidine base or analogue or derivative thereof R2 will be linked at the 9- or 1-position, respectively.
By xe2x80x9cpurine or pyrimidine basexe2x80x9d or an analogue or derivative thereof is meant a purine or pyrimidine base found in native nucleosides or an analogue thereof which mimics such bases in that their structures (the kinds of atoms and their arrangement) are similar to the native bases but may either possess additional or lack certain of the functional properties of the native bases. Such analogues include those derived by replacement of a CH2 moiety by a nitrogen atom (for example, 5-azapyrimidines such as 5-azacytosine) or vice verse (for example 7-deazapurines, for example 7-deazadenosine or 7-deazaguanosine) or both (e.g., 7-deaza-8-azapurines). By derivatives of such bases or analogues are meant those compounds wherein ring substituents are either incorporated, removed or modified by conventional substituents known in the art, e.g., halogen, hydroxyl, amino, C1-6 alkyl. Such purine or pyrimidine bases, analogues and derivatives will be well known to those skilled in the art.
Conveniently the group R2 is selected from: 
wherein R3 is selected from the group of hydrogen, acetyl, hydroxyl or C1-6 alkyl or alkenyl groups;
R4 and R5 are independently selected from the group of hydrogen, hydroxymethyl, trifluoromethyl, substituted or unsubstituted C1-6 alkyl or alkenyl groups, bromine, chlorine, fluorine, or iodine; R6 is selected from the group of hydrogen, cyano, carboxy, ethoxycarbonyl, carbamoyl, or thiocarbamoyl; and
X and Y are independently selected from the group of hydrogen, bromine, chlorine, fluorine, iodine, amino or hydroxy groups.
Preferably R2 is 
wherein R3 and R4 are as defined hereinabove.
Z is preferably xe2x80x94Sxe2x80x94.
When the compound of formula (I) is a 1,3-oxathiolane of formula (Ia), where Z is S, Sxe2x95x90O or SO2, 
preferably:
R1 is selected from a group consisting of hydrogen and an acyl group having 1 to 16 carbon atoms;
R2 is a heterocyclic radical selected from the group consisting of: 
xe2x80x83R3 and R4 are independently selected from the group consisting of hydrogen and C1-6 alkyl groups;
R5 is selected from the group consisting of hydrogen, C1-6 alkyl, bromine, chlorine, fluorine, and iodine; and
X and Y are independently selected from the group consisting of bromine, chlorine, fluorine, iodine, amino and hydroxyl groups.
When the compound of formula (I) is a 1,3-dioxolane of formula (Ib), 
preferably:
R1 is selected from the group consisting of hydrogen, an aliphatic acyl group having 1 to 16 carbon atoms, benzoyl and benzoyl substituted in any position by a halogen, a lower alkyl, a lower alkoxy, a nitro or a trifluoromethyl group;
R2 is a heterocyclic radical selected from the group consisting of: 
wherein:
R3 is selected from the group consisting of hydrogen and lower alkyl radicals having from 1 to 3 carbon atoms;
R4 is selected from the group consisting of hydrogen, lower alkyl and alkenyl radicals having from 1 to 3 carbon atoms; and
R5 is selected from the group consisting of lower alkyl and alkenyl radicals having from 1-3 carbon atoms, fluoro and iodo.
By xe2x80x9ca pharmaceutically acceptable derivativexe2x80x9d is meant any pharmaceutically acceptable salt, ester, or salt of such ester, of a compound of formula (I) or any other compound which, upon administration to the recipient, is capable of providing (directly or indirectly) a compound of formula (I) or an antivirally active metabolite or residue thereof.
It will be appreciated by those skilled in the art that the compounds of formula (I) may be modified to provide pharmaceutically acceptable derivatives thereof, at functional groups in both the base moiety, R2, and at the hydroxymethyl group of the oxathiolane or dioxolane ring. Modification at all such functional groups is included within the scope of the invention. However, of particular interest are pharmaceutically acceptable derivatives (e.g., esters) obtained by modification of the 2-hydroxymethyl group of the oxathiolane or dioxolane ring.
Preferred esters of the compounds of formula (I) include the compounds in which R1 is replaced by a carboxyl function 
in which the non-carbonyl moiety R of the ester grouping is selected from hydrogen, straight or branched chain alkyl (e.g., methyl, ethyl, n-propyl, t-butyl, n-butyl), alkoxyalkyl (e.g., methoxymethyl), aralkyl (e.g., benzyl), aryloxyalkyl (e.g., phenoxymethyl), aryl (e.g., phenyl optionally substituted by halogen, C1-4 alkyl or C1-4 alkoxy); substituted dihydro pyridinyl (e.g., N-methyldihydro pyridinyl); sulphonate esters such as alkyl- or aralkylsulphonyl (e.g., methanesulphonyl); sulfate esters; amino acid esters (e.g., L-valyl or L-isoleucyl) and mono-, di- or tri-phosphate esters.
Also included within the scope of such esters are esters derived from polyfunctional acids such as carboxylic acids containing more than one carboxyl group, for example, dicarboxylic acids HO2C(CH2)nCO2H where n is an integer of 1 to 10 (for example, succinic acid) or phosphoric acids. Methods for preparing such esters are well known. See, for example, Hahn et al., xe2x80x9cNucleotide Dimers as Anti-Human Immunodeficiency Virus Agentsxe2x80x9d, Nucleotide Analooues, pp. 156-159 (1989) and Busso et al., xe2x80x9cNucleotide Dimers Suppress HIV Expression In Vitroxe2x80x9d, AIDS Research and Human Retroviruses, 4(6), pp. 449-455 (1988). Where esters are derived from such acids, each acidic group is preferably esterified by a compound of formula (I) or other nucleosides or analogues and derivatives thereof to provide esters of the formula (IV) where: 
W is 
and n is an integer of 1 to 10 or 
J is any nucleoside or nucleoside analog or derivative thereof and Z and R2 are as defined above. Among the preferred nucleosides and nucleoside analogues are 3xe2x80x2-azido-2xe2x80x23xe2x80x2-dideoxy-thymidine, 2xe2x80x2,3xe2x80x2-dideoxycytidine, 2xe2x80x2,3xe2x80x2-dideoxyadenosine, 2xe2x80x2,3xe2x80x2-dideoxyinosine, 2xe2x80x2,3xe2x80x2-dideoxythymidine, 2xe2x80x2,3xe2x80x2-dideoxy-2xe2x80x2,3xe2x80x2-didehydrothymidine, and 2xe2x80x2,3xe2x80x2-dideoxy-2xe2x80x2,3xe2x80x2-didehydrocytidine and ribavirin and those nucleosides whose bases are depicted on pages 7-8 of this specification. We most prefer a homodimer consisting of two nucleosides of formula (I).
With regard to the above described esters, unless otherwise specified, any alkyl moiety present advantageously contains 1 to 16 carbon atoms, preferably 1 to 4 carbon atoms and could contain one or more double bonds. Any aryl moiety present in such esters advantageously comprises a phenyl group.
In particular the esters may be a C1-16 alkyl ester, an unsubstituted benzoyl ester or a benzoyl ester substituted by at least one halogen (bromine, chlorine, fluorine or iodine), C1-6 alkyl or alkenyl, saturated or unsaturated C1-6 alkoxy, nitro or trifluoromethyl groups.
Pharmaceutically acceptable salts of the compounds of formula (1) include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic acids. Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.
Salts derived from appropriate bases include alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium and NR4+ (where R is C1-4 alkyl) salts.
References hereinafter to a compound according to the invention include both compounds of formula (I) and their pharmaceutically acceptable derivatives.
Specific compounds of formula (I) include:
Cis-2-hydroxymethyl-5-(cytosin-1xe2x80x2-yl)-1,3-oxathiolane, trans-2-hydroxymethyl-5-(cytosin-1xe2x80x2-yl)-1,3-oxathiolane, and mixtures thereof;
Cis-2-benzoyloxymethyl-5-(cytosin-1xe2x80x2-yl)-1,3-oxathiolane, trans-2-benzoyloxymethyl-5-(cytosin-1xe2x80x2-yl)-1,3-oxathiolane, and mixtures thereof;
Cis-2-hydroxymethyl-5-(N4xe2x80x2-acetyl-cytosin-1xe2x80x2-yl)-1,3-oxathiolane, trans-2-hydroxymethyl-5-(N4xe2x80x2-acetyl-cytosin-1xe2x80x2-yl)-1,3-oxathiolane, and mixtures thereof;
Cis-2-benzoyloxymethyl-5-(N4xe2x80x2-acetyl-cytosin-1xe2x80x2-yl)-1,3-oxathiolane, trans-2-benzoyloxymethyl-5-(N4xe2x80x2-acetyl-cytosin-1xe2x80x2-yl)-1,3-oxathiolane, and mixtures thereof; and
Cis-2-hydroxymethyl-5-(cytosin-1xe2x80x2-yl)-3-oxo-1,3-oxathiolane;
Cis-2-hydroxymethyl-5-(N,Nxe2x80x2-dimethylamino-methylene cytosin-1xe2x80x2-yl)-1,3-oxathiolane;
Cis-2-succinyloxymethyl-5-(cytosin-1xe2x80x2-yl)-1,3-oxathiolane;
Cis-2-benzoyloxymethyl-5-(6xe2x80x2-chloropurin 9xe2x80x2-yl)-1,3-oxathiolane; trans-2-benzoyloxymethyl-5-(6xe2x80x2-chloropurin-N-9xe2x80x2-yl)-1,3-oxathiolane, and mixtures thereof;
Cis-2-hydroxymethyl-5-(6xe2x80x2-hydroxypurin-9xe2x80x2-yl)-1,3-oxathiolane; trans-2-hydroxymethyl-5-(6xe2x80x2-hydroxypurin-9xe2x80x2-yl)-1,3-oxathiolane; and mixtures thereof;
Cis-2-benzoyloxymethyl-5-(uracil-N-1xe2x80x2-yl)-1,3-oxathiolane, trans-2-benzoyloxymethyl-5-(uracil-1xe2x80x2-yl)-1,3-oxathiolane, and mixtures thereof;
Cis-2-hydroxymethyl-5-(uracil-1xe2x80x2-yl)-1,3-oxathiolane;
Cis-2-benzoyloxymethyl-5-(thymin-1xe2x80x2-yl)-1,3-oxathiolane, trans-2-benzoyloxymethyl-5-(thymin-1xe2x80x2-yl)-1,3-oxathiolane, and mixtures thereof;
Cis-2-hydroxymethyl-5-(thymin-1xe2x80x2-yl)-1,3-oxathiolane;
Cis-2-hydroxymethyl-5-(adenin-9xe2x80x2-yl)-1,3-oxathiolane, trans-2-hydroxymethyl-5-(adenin-9xe2x80x2-yl)-1,3-oxathiolane, and mixtures thereof;
Cis-2-hydroxethyl-5-(inosin-9xe2x80x2-yl)-1,3-oxathiolane, trans-2-hydroxymethyl-5-(inosin-9xe2x80x2-yl)-1,3-oxathiolane, and mixtures thereof;
Cis-2-benzoyloxymethyl-5-(N4xe2x80x2-acetyl-5xe2x80x2-fluorocytosin-1-yl)-1,3-oxathiolane, trans-2-benzoyloxymethyl-5-(N4xe2x80x2-acetyl-5xe2x80x2-fluorocytosin-1xe2x80x2-yl)-1,3-oxathiolane, and mixtures thereof;
Cis-2-hydroxymethyl-5-(5xe2x80x2-fluorocytosin-1xe2x80x2-yl)-1,3-oxathiolane, trans-2-hydroxymethyl-5-(5xe2x80x2-fluorocytosin-1xe2x80x2-yl)-1,3-oxathiolane, and mixtures thereof;
Cis-2-acetoxymethyl-4-(thymin-1xe2x80x2-yl)-1,3-dioxolane, trans-2-acetoxymethyl-4-(thymin-1xe2x80x2-yl)-1,3-dioxolane, and mixtures thereof;
Cis-2-hydroxymethyl-4-(thymin-1xe2x80x2-yl)-1,3-dioxolane, trans-2-hydroxymethyl-4-(thymin-1xe2x80x2-yl)-1,3-dioxolane, and mixtures thereof;
Cis-2-benzoyloxymethyl-4-(cytosin-1xe2x80x2-yl)-1,3-dioxolane, trans-2-benzoyloxymethyl-4-(cytosin-1xe2x80x2-yl)-1,3 dioxolane, and mixtures thereof;
Cis-2-hydroxymethyl-4-(cytosin-1-yl)-1,3-dioxolane, trans-2-hydroxymethyl-4-(cytosin-1xe2x80x2-yl)-1,3-dioxolane, and mixtures thereof;
Cis-2-benzoyloxymethyl-4-(adenin-9xe2x80x2-yl)-1,3-dioxolane, trans-2-benzoyloxymethyl-4-(adenin-9xe2x80x2-yl)-1,3-dioxolane, and mixtures thereof;
Cis-2-hydroxymethyl-4-(adenin-9xe2x80x2-yl)-1,3-dioxolane, trans-2-hydroxymethyl-4-(adenin-9xe2x80x2-yl)-1,3-dioxolane, and mixtures thereof;
Cis-2-benzoyloxylmethyl-4-(2xe2x80x2-amino-6xe2x80x2-chloro-purin-9xe2x80x2-yl)-1,3-dioxolane, trans-2-benzoyloxylmethyl-4-(2xe2x80x2-amino-6xe2x80x2-chloro-purin-9xe2x80x2-yl)-1,3-dioxolane, and mixtures thereof;
Cis-2-hydroxymethyl-4-(2xe2x80x2-amino-6xe2x80x2-chloro-purin-9xe2x80x2-yl)-1,3-dioxolane, trans-2-hydroxymethyl-4-(2xe2x80x2-amino-6xe2x80x2-chloro-purin-9xe2x80x2-yl)-1,3-dioxolane, and mixtures thereof;
Cis-2-hydroxymethyl-4-(2xe2x80x2-amino-purin-9xe2x80x2-yl)-1,3-dioxolane, trans-2-hydroxymethyl-4-(2xe2x80x2-amino-purin-9xe2x80x2-yl)-1,3-dioxolane, and mixtures thereof;
Cis-2-hydroxymethyl-4-(2xe2x80x2,6xe2x80x2-diamino-purin-9xe2x80x2-yl)-1,3-dioxolane, trans-2-hydroxymethyl-4-(2xe2x80x2,6xe2x80x2-diamino-purin-9xe2x80x2-yl)-1,3-dioxolane, and mixtures thereof;
Cis-2-hydroxymethyl-4-(guanin-9xe2x80x2-yl)-1,3-dioxolane, trans-2-hydroxymethyl-4-(guanin-9xe2x80x2-yl)-1,3-dioxolane, and mixtures thereof;
Cis-2-hydroxymethyl-5-(N,N-dimethylamino methylene cytosin-1xe2x80x2-yl)-1,3-dioxolane, trans-2-hydroxymethyl-4-(N,N-dimethylamino methylene cytosin-1xe2x80x2-yl)-1,3-dioxolane, and mixtures thereof;
in the form of a racemic mixture or a single enantiomer.
The compounds of the invention either themselves possess antiviral activity and/or are metabolizable to such compounds. In particular these compounds are effective in inhibiting the replication of retroviruses, including human retroviruses such as human immunodeficiency viruses (HIV""s), the causative agents of AIDS.
There is thus provided as a further aspect of the invention a compound formula (I) or a pharmaceutically acceptable derivative thereof for use as an active therapeutic agent in particular as an antiviral agent, for example in the treatment of retroviral infections.
In a further or alternative aspect there is provided a method for the treatment of a viral infection, in particular an infection caused by a retrovirus such as HIV, in a mammal, including man, comprising administration of an effective amount of an antiviral compound of formula (I) or a pharmaceutically acceptable derivative thereof.
There is also provided in a further or alternative aspect of this invention, use of a compound of formula (I) or a pharmaceutically acceptable derivative thereof for the manufacture of a medicament for the treatment of a viral infection.
The compounds of the invention are also useful in the treatment of AIDS-related conditions such as AIDS-related complex (ARC), persistent generalized lymphadenopathy (PGL), AIDS-related neurological conditions (such as dementia), anti-HIV antibody-positive and HIV-positive conditions, Kaposi""s sarcoma, thrombocytopenia purpurea and opportunistic infections.
The compounds of the invention are also useful in the prevention or progression to clinical illness of individuals who are anti-HIV antibody or HIV-antigen positive and in prophylaxis following exposure to HIV.
The compounds of formula (I) or the pharmaceutically acceptable derivatives thereof, may also be used for the prevention of viral contamination of biological fluids such as blood or semen in vitro.
Certain of the compounds of formula (I) are also useful as intermediates in the preparation of other compounds of the invention.
It will be appreciated by those skilled in the art that references herein to treatment extends to prophylaxis as well as the treatment of established infections or symptoms.
It will be further appreciated that the amount of a compound of the invention required for use in treatment will vary not only with the particular compound selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian. In general, however, a suitable dose will be in the range from about 1 to about 750 mg/kg of body weight per day, such as 3 to about 120 mg per kilogram body weight of the recipient per day, preferably in the range of 6 to 90 mg/kg/day, most preferably in the range of 15 to 60 mg/kg/day.
The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example as two, three, four or more sub-doses per day.
The compound is conveniently administered in unit dosage form; for example containing 10 to 1500 mg, conveniently 20 to 1000 mg, most conveniently 50 to 700 mg of active ingredient per unit dosage form.
Ideally the active ingredient should be administered to achieve peak plasma concentrations of the active compound of from about 1 to 75 xcexcM, preferably about 2 to 50 xcexcM, most preferably about 3 to about 30 xcexcM. This may be achieved, for example, by the intravenous injection of a 0.1 to 5% solution of the active ingredient, optionally in saline, or administered as a bolus containing about 0.1 to about 110 mg/kg of the active ingredient. Desirable blood levels may be maintained by a continuous infusion to provide about 0.01 to about 5.0 mg/kg/hour or by intermittent infusions containing about 0.4 to about 15 mg/kg of the active ingredient.
While it is possible that, for use in therapy, a compound of the invention may be administered as the raw chemical it is preferable to present the active ingredient as a pharmaceutical formulation.
The invention thus further provides a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof together with one or more pharmaceutically acceptable carriers thereof and, optionally, other therapeutic and/or prophylactic ingredients. The carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
Pharmaceutical formulations include those suitable for oral, rectal, nasal, topical (including buccal and sub-lingual), vaginal or parenteral (including intramuscular, sub-cutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation. The formulations may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the active compound with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
Pharmaceutical formulations suitable for oral administration may conveniently be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution; as a suspension; or as an emulsion. The active ingredient may also be presented as a bolus, electuary or paste. Tablets and capsules for oral administration may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, or wetting agents. The tablets may be coated according to methods well known in the art. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils) or preservatives.
The compounds according to the invention may also be formulated for parenteral administration (e.g., by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.
For topical administration to the epidermis, the compounds according to the invention may be formulated as ointments, creams or lotions, or as a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.
Formulations suitable for topical administration in the mouth include lozenges comprising active ingredient in a flavored based, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
Pharmaceutically formulations suitable for rectal administration wherein the carrier is a solid, are most preferably represented as unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art, and the suppositories may be conveniently formed by admixture of the active compound with the softened or melted carrier(s) followed by chilling and shaping in molds.
Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient, such carriers as are known in the art to be appropriate.
For intra-nasal administration the compounds of the invention may be used as a liquid spray or dispersible powder or in the form of drops.
Drops may be formulated with an aqueous or non-aqueous base also comprising one or more dispersing agents, solubilizing agents or suspending agents. Liquid sprays are conveniently delivered from pressurized packs.
For administration by inhalation, the compounds according to the invention are conveniently delivered from an insufflator, nebulizer or a pressurized pack or other convenient means of delivering an aerosol spray. Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount.
Alternatively, for administration by inhalation or insufflation, the compounds according to the invention may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form in, for example, capsules or cartridges or, e.g., gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.
When desired, the above described formulations adapted to give sustained release of the active ingredient, may be employed.
The pharmaceutical compositions according to the invention may also contain other active ingredients such as antimicrobial agents, or preservatives.
The compounds of the invention may also be used in combination with other therapeutic agents, for example, other antiinfective agents. In particular the compounds of the invention may be employed together with known antiviral agents.
The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a physiologically acceptable derivative thereof together with another therapeutically active agent, in particular, an antiviral agent.
The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier thereof comprise a further aspect of the invention.
Suitable therapeutic agents for use in such combinations include acyclic nucleosides such as acyclovir, ganciclovir, interferons such as alpha-, beta-and gamma-interferon; glucuronation inhibitors such as probenecid; nucleoside transport inhibitors such as dipyridamole; nucleoside analogues such as 3xe2x80x2-azido-2xe2x80x2,3xe2x80x2-dideoxythymidine, 2xe2x80x2,3xe2x80x2-dideoxycytidine, 2xe2x80x2,3xe2x80x2-dideoxyadenosine, 2xe2x80x2,3xe2x80x2-dideoxyinosine, 2xe2x80x2,3xe2x80x2-dideoxythymidine, 2xe2x80x2,3xe2x80x2-dideoxy-2xe2x80x2,3xe2x80x2-didehydrothymidine, and 2xe2x80x2,3xe2x80x2-dideoxy-2xe2x80x2,3xe2x80x2-didehydrocytidine and ribavirin; immunomodulators such as interleukin II (IL2) and granulocyte macrophage colony stimulating factor (GM-CSF), erythropoietin, ampligen, thymomodulin, thymopentin, foscarnet, glycosylation inhibitors such as 2-deoxy-D-glucose, castanospermine, 1-deoxynojirimycin; and inhibitors of HIV binding to CD4 receptors such as soluble CD4, CD4 fragments and CD4-hybrid molecules.
The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.
When the compound of formula (I) or a pharmaceutically acceptable derivative thereof is used in combination with a second therapeutic agent active against the same virus, the dose of each compound may be either the same or differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.
In the processes for preparing the compounds of this invention, the following definitions are used:
R1 is a hydrogen, an acyl group having from 1 to 16 carbon atoms, or a hydroxyl protecting group;
R2 is a purine or pyrimidine base or an analogue or derivative thereof;
Rx is substituted or unsubstituted C1-6 alkyl;
Ry is substituted or unsubstituted C1-6 alkyl or substituted or unsubstituted aryl;
Rz is halo, such as bromo, chloro, iodo or fluoro; and
R is a substituted or unsubstituted, saturated or unsaturated alkyl group, e.g., a C1-6 alkyl or alkenyl group (such as methyl, ethyl, propyl, butyl, ethenyl, propenyl, allyl, butenyl, etc.); a substituted or unsubstituted aliphatic or aromatic acyl group, e.g., a C1-6 aliphatic acyl group such as acetyl or an aromatic acyl group such as benzoyl; a substituted or unsubstituted, saturated or unsaturated alkoxy or aryloxy carbonyl group, such as methyl carbonate and phenyl carbonate; substituted or unsubstituted sulphonyl imidazolide; substituted or unsubstituted aliphatic or aromatic amino carbonyl group, such as phenyl carbamate; substituted or unsubstituted alkyl imidate group such as trichloroacetamidate; substituted or unsubstituted, saturated or unsaturated phosphonate, such as diethylphosphonate; substituted or unsubstituted aliphatic or aromatic sulphonyl group, such as tosylate; or hydrogen.
Oxathiolane compounds of formula (Ia), i.e., compounds of formula (I) wherein Z is S, Sxe2x95x90O or SO2, and their pharmaceutically acceptable derivatives may be prepared according to the processes discussed herein or by any method known in the art for the preparation of compounds of analogous structure.
One process according to the invention is illustrated in SCHEME 1. Although this process is illustrated using specific reagents and compounds, it will be obvious to one of skill in the art that suitable alternative reactants may be used to prepare analogous products as depicted, for example, in SCHEME 1A.
The various steps involved in the synthesis as illustrated in SCHEME 1 may be briefly described as follows: 
Step 1: Commercial bromoacetaldehyde diethyl acetal (or an analogous halo alkyl acetal of the formula RzCH2(ORx)2), is treated in boiling DMF with an excess of potassium thiobenzoate to give the benzoylthio acetal of formula (V).
Step 2: The benzoyl group of formula (V) is hydrolyzed with sodium hydroxide in an aqueous organic solvent to give the known mercaptoacetal shown in formula (VI) (G. Hesse and I. Jorder, xe2x80x9cMercaptoacetaldehyde and dioxy-1,4-dithianexe2x80x9d, Chem. Ber., 85, pp. 924-32 (1952)).
Step 3: Glycerol 1-monobenzoate prepared according to the literature (E. G. Hallonquist and H. Hibbert, xe2x80x9cStudies on reactions relating to carbohydrates and polysaccharides. Part XLIV: Synthesis of isomeric bicyclic acetal ethersxe2x80x9d, Can. J. Research, 8, pp. 129-36 (1933)), is oxidized with sodium meta-periodate to give the known benzoyloxyacetaldehyde of formula (VII) (C. D. Hurd and E. M. Filiachione, xe2x80x9cA new approach to the synthesis of aldehyde sugarsxe2x80x9d, J. Am. Chem. Soc., 61, pp. 1156-59 (1939)).
Step 4: The aldehyde of formula (VII) or any aldehyde of the formula RyCOOCH2CHO is then condensed with the mercaptoacetal of formula (VI) or any mercaptoacetal of the formula HSCH2CH(ORX)2 in a compatible organic solvent, such as toluene, containing a catalytic amount of a strong acid to give the novel intermediate shown in formula (VIII).
Step 5: The 1,3-oxathiolane of formula (VIII) is then reacted with a purine or pyrimidine base (e.g., cytosine) previously silylated with, for example, hexamethyldisilazane in a compatible solvent using a Lewis acid or trimethylsilyl triflate to give intermediate of formula (IX).
Step 6: The amine function of the compound shown in formula (IX) is acetylated with acetic anhydride to yield the intermediate of formula (X) as cis- and trans-isomers which are separated, preferably by fractional crystallization, to give pure cis- (X) and pure trans- (X).
Step 7: The cis- or trans- isomers of formula (X) are treated with methanolic ammonia to obtain the desired product shown in formula (XI) as cis- and trans-isomers.
Step 8: The preceding isomers of formula (XI) are treated with an oxidizing agent which may be a suitable peracid in a compatible solvent to give the 3-oxide (sulfoxide) of formula (XII).
This synthesis is applicable to any nucleoside base analogue, as would be obvious to those skilled in the art of nucleoside chemistry. Other compounds defined by formula (Ia) may be obtained similarly from intermediate VII by using the appropriate heterocyclic compound in place of cytosine in Step 5. In Step 4, other esters of hydroxyacetaldehyde such as aliphatic acyl or substituted aroyl groups can be used following the same sequence of steps leading to the compounds of formula (XI) and formula (XII), respectively.
A second process according to this invention for producing oxathiolane compounds is illustrated in SCHEME 2. Although this process is illustrated using specific reagents and compounds, it will be obvious to one of skill in the art that suitable analogous reactants may be used to prepare analogous products, as depicted, for example, in SCHEME 2A.
The various steps involved in the synthesis as illustrated in SCHEME 2 may be briefly described as follows: 
Step 1: A mercaptoacetaldehyde monomer produced from the dimer in a solvent such as pyridine is reacted directly with a benzoyloxyacetaldehyde of formula (VII) or any aldehyde of the formula RyCOOCH2CHO to yield an oxathiolane lactol of formula (XIII).
Step 2: The hydroxyl group of the compound of formula (XIII) is converted to a leaving group with a suitable reagent such as acetyl chloride in a compatible organic solvent to yield an important oxathiolane intermediate of formula (XIV).
Step 3: The oxathiolane intermediate of formula (XIV) is reacted with a previously silylated purine or pyrimidine base to give, for example, a cytosin-1xe2x80x2-yl oxathiolane of formula (IX).
Step 4: The amine function of the compound shown in formula (IX) is acylated with acetic anhydride in a solvent such as pyridine to yield a compound of formula (X) which provides for easier separation of isomers.
Step 5: The benzoate and acetyl functions of the compound of formula (X) are hydrolyzed under basic conditions to yield an oxathiolane of formula (XI).
A third process for producing oxathiolane compounds is illustrated in SCHEME 3. Although this process is illustrated using specific reagents and compounds, it will be obvious to one of skill in the art that suitable analogous reactants may be used to prepare analogous products, as depicted, for example, in SCHEME 3A.
The various steps involved in the synthesis as illustrated in SCHEME 3 may be briefly described as follows: 
Step 1: Mercaptoacetaldehyde monomer produced from the dimer in a solvent such as pyridine is reacted directly with ethyl glyoxylate or any organic glyoxylate of the formula RyOOCCHO to yield an oxathiolane lactol of formula (XV).
Step 2: The hydroxyl group of the compound of formula (XV) is converted to a leaving group with a suitable reagent such as acetyl chloride in a compatible organic solvent to yield an important oxathiolane intermediate of formula (XVI).
Step 3: The oxathiolane intermediate of formula (XVI) is reacted with a previously silylated purine or pyrimidine base, e.g., uracil, in the presence of a Lewis acid or preferably trimethylsilyl iodide to give, e.g., a uracil-1xe2x80x2-yl oxathiolane of formula (XVII) predominantly as the cis-isomer.
Step 4: The ester group of the oxathiolane of formula (XVII) is selectively reduced with a suitable reducing agent such as sodium borohydride in a compatible organic solvent such as methanol to yield an oxathiolane nucleoside of formula (XVIII).
Step 5: The hydroxyl group of the compound of formula (XVIII) is protected with a suitable silyl protecting group such as t-butyl-dimethyl silyl in an appropriate solvent such as dimethyl formamide (DMF) to yield an oxathiolane of formula (XIX).
Step 6: The uracil base of formula (XIX) can be interconverted to another base, such as cytosine, by reaction with a suitable reagent such as p-chlorophenoxy phosphorous oxychloride followed by amination with, e.g., ammonia in methanol to yield an oxathiolane of formula (XX).
Step 7: The silyl group of the compound of formula (XX) is removed under neutral conditions using a suitable reagent such as tetra n-butyl ammonium fluoride in a suitable solvent such as tetrahydrofuran to yield the oxathiolane of formula (XI).
A fourth process according to this invention for producing oxathiolane compounds is illustrated in SCHEME 4. Although this process is illustrated using specific reagents and compounds, it will be obvious to one of skill in the art that suitable analogous reactants may be used to prepare analogous products, as depicted, for example, in SCHEME 4A.
The various steps involved in the synthesis as illustrated in SCHEME 4 may be briefly described as follows: 
Step 1: The hydroxyl group of the intermediate of formula XV, or corresponding Ry-substituted intermediate (see SCHEME 3, step 1), is converted to a leaving group with a suitable reagent such as methyl chloroformate in a compatible organic solvent to yield an important intermediate of formula (XXI).
Step 2: The ester group of the intermediate of formula (XXI) is selectively reduced with a suitable reducing agent such as sodium borohydride in a compatible organic solvent such as methanol and the resultant hydroxyl group is directly protected with a suitable group such as t-butyl diphenyl silyl to yield an oxathiolane of formula (XXII).
Step 3: The oxathiolane of formula (XXII) is reacted with a previously silylated purine or pyrimidine base, such as cytosine to give, e.g., a cytosin-1xe2x80x2-yl oxathiolane of formula (XXIII).
Step 4: The amine function of the compound shown in formula (XXIII) is acylated, e.g., with acetic anhydride in a solvent such as pyridine to yield a compound of formula (XXIV) which provides for easier separation of isomers.
Step 5: The silyl and acetyl functions of the compound of formula (XXIV) are hydrolyzed under basic conditions to yield an oxathiolane of formula (XI).
In a fifth process the oxathiolane compounds of formula (Ia), in which Z is S, Sxe2x95x90O or SO2, may be prepared by the reaction of a compound of formula (LIX) 
with a compound of formula (LX) 
wherein P is a protecting group, followed by removal of the protecting group. The compounds of formula (LIX) may be prepared for reaction by a suitable epoxide (LXI) 
with an appropriate sulphur-containing compound, e.g., sodium thioacetate. Compounds of formula (LXI) are either known in the art or may be obtained by analagous processes.
In a sixth process of this invention, the oxathiolane compounds of formula (Ia) may be made by converting an intermediate of formula (LXII) 
to a compound of formula (Ia) by conversion of the anomeric NH2 to the desired purine or pyrimidine base by methods well known in the art of nucleoside chemistry.
The dioxolane compounds of formula (Ib) and their pharmaceutically acceptable derivatives may be prepared by the processes according to this invention or by any method known in the art for preparation of compounds of analogous structure.
One such process for preparing dioxolane compounds of formula (Ib) is outlined in SCHEME 5. Although this process is illustrated using specific reagents and compounds, it will be obvious to one of skill in the art that suitable alternative reactants may be used to prepare analogous products, as depicted, for example, in SCHEME 5A.
The various steps involved in the synthesis illustrated in SCHEME 5 may be briefly described as follows: 
Step 1: Chloroacetaldehyde diethyl acetal (or an analogous halo alkyl acetal) is treated with glycerol in an inert solvent according to the procedure reported by E. G. Hallonquist and H. Hibbert, xe2x80x9cStudies In Reactions Relating To Carbohydrates And Polysaccharidesxe2x80x94Part XLIV: Synthesis Of Isomeric Bicyclic Acetal Ethersxe2x80x9d, Can. J. Res., 8, pp. 129-136 (1933) to produce an intermediate of formula (XXV).
Step 2: The primary alcohol function of the dioxolane intermediate of formula (XXV) is treated with an oxidizing reagent such as chromic acid (which may be complexed with pyridine) in a compatible organic solvent to give the corresponding dioxolane carboxylic acid of formula (XXVI).
Step 3: The acid of formula (XXVI) is converted to a mixed anhydride using an alkyl chloroformate and subjected to a Baeyer-Villiger oxidation with an organic peracid such as m-chloroperbenzoic acid to yield the corresponding aroyloxydioxolane of formula (XXVII).
Step 4: Intermediate of formula (XXVII) is then reacted with previously silylated purine or pyrimidine base such as thymine, with, e.g., hexamethyldisilazane in a compatible solvent and the reaction catalyzed by a Lewis acid or preferably by trimethylsilyl triflate to give, e.g., the thymin-1xe2x80x2-yl dioxolane of formula (XVI).
Step 5: The chlorine atom of formula (XXVIII) is displaced by reaction with a benzoic acid salt in a compatible solvent such as dimethyl formamide to give an intermediate of formula (XXIX).
Step 6: The benzoate ester function is then hydrolyzed under basic conditions to yield the desired end-product of formula (XXX).
A second process for preparing further specific dioxolane compounds of the present invention is illustrated in SCHEME 6. Although this process is illustrated using specific reagents and compounds, it will be obvious to one of skill in the art that suitable alternative reactants may be used to prepare analogous products, as depicted, for example, in SCHEME 6A.
The various steps involved in the synthesis illustrated in SCHEME 6 may be briefly described as follows: 
Step 1: The chlorine atom of starting dioxolane of formula (XXV) is displaced by a benzoic (or acetic) acid salt in a solvent such a dimethylformamide to yield the diol monoester of formula (XXXI).
Step 2: The hydroxymethyl group of formula (XXXI) is oxidized with a suitable reagent such as chromic acid (which may be complexed with pyridine) in a compatible organic solvent to give the dioxolane carboxylic acid of formula (XXXII).
Step 3: The acid of formula (XXXII) is then subjected to Baeyer-Villiger oxidation by the procedure outlined in Step 2 of SCHEME 5 above to give the corresponding aroyloxy-dioxolane of formula (XXXIII). Step 4: The intermediate of formula (XXXIII) is reacted with a previously silyated purine or pyrimidine base, such as cytosine, under the reaction conditions outlined in Step 3 of SCHEME 5 to give, e.g., the cytosin-1xe2x80x2-yl dioxolane of formula (XXXIV).
Step 5: The amine function of formula (XXXIV) is acylated with acetic anhydride in a solvent such as pyridine to give the compound of formula (XXXV) which provides for easier separation of isomers.
Step 6: The ester and acetyl functions of formula (XXXV) are hydrolyzed under basic conditions to yield the desired end-product of formula (XXXVI).
Step 7: ((XXXIII) to (XXXVII)) The intermediate of formula (XXXIII) is alternatively reacted with a purine or pyrimidine base, such as adenine, by the procedure outlined above in Step 3 of SCHEME 5 to give the compound of formula (XXXVII).
Step 8: ((XXXVII) to (XXXVIII)) The ester function of formula (XXXVII) is hydrolyzed under basic conditions to yield the desired end-product of formula (XXXVIII).
Step 9: ((XXXIII) to (XXXIX)) The intermediate of formula (XXXIII) is alternatively reacted with 2-amino-6-chloropurine under the conditions outlined in Step 3 of SCHEME 5 to give a compound of formula (XXXIX).
Step 10: ((XXXIX) to (XL)) The intermediate (XXXIX) is hydrolyzed under basic conditions to yield the desired end-product of formula (XL).
Step 11: ((XL) to (XLI)) The chlorine atom of formula (XL) is removed by catalytic hydrogenation over Pd/C to give the 2xe2x80x2-amino-purin-9xe2x80x2-yl dioxolane of formula (XLI).
Step 12: The above intermediate (XXXIX) is alternatively reacted with excess ammonia under pressure whereupon the 2xe2x80x2,6xe2x80x2-diamino-purin-9xe2x80x2-yl dioxolane of formula (XLII) is produced.
Step 13: The compound of formula (XL) is alternatively subjected to boiling sodium hydroxide to give the desired end-product guanin-9xe2x80x2-yl dioxolane of formula (XLIII).
A third process for preparing dioxolane compounds of the present invention is illustrated in SCHEME 7. Although this process is illustrated using specific reagents and compounds, it will be obvious to one of skill in the art that suitable alternative reactants may be used to prepare analogous products, as depicted, for example, in SCHEME 7A.
The various steps involved in the synthesis illustrated in SCHEME 7 may be briefly described as follows: 
Step 1: Benzoyloxyacetaldehyde (or any aldehyde of the formula RyCOOCH2CHO) is converted to the bis(2-methoxyethyl)acetal of formula (XLIV) in, e.g., boiling toluene in the presence of a Lewis acid.
Step 2: The benzoyl group of formula (XLIV) is hydrolyzed with, e.g., potassium carbonate in an aqueous organic solvent to give the hydroxyacetal shown in formula (XLV).
Step 3: The aldehyde of formula (VII) or any aldehyde of the formula RyCOOCH2CHO is condensed with the hydroxyacetal of formula (XLV) or any hydroxyacetal of the formula HSCH2CH(ORX)2 in a compatible organic solvent, such as toluene, containing a catalytic amount of a strong acid to give the novel intermediate of formula (XLVI).
Step 4: The 1,3-dioxolane of formula (XLVI) is then reacted with a previously silylated purine or pyrimidine base, such as cytosine, with, e.g., hexamethyldisilazane in a compatible solvent using a Lewis acid such as titanium tetrachloride to give the intermediate of formula (XXXIV).
Step 5: The amine function of the compound of formula (XXIV) is acetylated with acetic anhydride to yield the intermediate (XXXV) for easier separation of cis- and trans-isomers.
Step 6: The cis- and/or trans-isomers of formula (XXXV) are treated with, e.g., methanolic ammonia to give the desired product shown in formula (XXXVI) as cis- and trans-isomers.
A preferred process for preparing dioxolane compounds of the present invention is illustrated in SCHEME 8. Although this process is illustrated using specific reagents and compounds, it will be obvious to one of skill in the art that suitable alternative reactants may be used to prepare analogous products, as depicted, for example, in SCHEME 8A.
The various steps involved in the synthesis illustrated in SCHEME 8 may be briefly described as follows: 
Step 1: The aldehyde of formula (VII) or any aldehyde of the formula RyCOOCH2CHO is condensed with the known epoxide described in R. L. Wasson and H. O. House, xe2x80x9cPreparation of Isophorone Oxidexe2x80x9d, Organic Synthesis Collective, Vol. IV, p. 552 (1963) in an appropriate solvent such as benzene and a suitable Lewis acid such as tetraethylammonium bromide to give dioxolane of formula (XLVIII).
Step 2: The ketone of formula (XLVIII) is subjected to a Baeyer-Willinger oxidation with an organic peracid such as m-chloroperbenzoic acid to yield the corresponding acetoxydioxolane (XLIX).
Step 3: The dioxolane of formula (XLIX) is then reacted with a previously silylated purine or pyrimidine base, such as cytosine, with, e.g., hexamethyldisilazane in a suitable solvent using a Lewis acid or preferrably trimethylsilyl triflate to give the intermediate of formula (XXXIV).
Step 4: The amine function of the compound of formula (XXIV) is acetylated with, e.g., acetic anhydride to yield the intermediate (XXXV) for easier separation of cis- and trans-isomers.
Step 5: The cis- and/or trans-isomers of formula (XXXV) are treated with methanolic ammonia to give the desired product shown in formula (XXXVI) as cis- and trans-isomers.
In the above-identified processes for making the oxathiolane and dioxolane compounds of this invention, the following intermediates are of particular importance:
2-thiobenzoylacetaldehyde diethylacetal (V);
cis- and trans-2-benzoyloxymethyl-5-ethoxy-1,3-oxathiolane (VIII);
cis- and trans-2-benzoyloxymethyl-5-hydroxy-1,3-oxathiolane (XIII);
cis- and trans-2-benzoyloxymethyl-5-acetoxy-1,3-oxathiolane (XIV);
cis- and trans-2-ethoxycarbonyl-5-hydroxy-1,3-oxathiolane (XV);
cis- and trans-2-ethoxycarbonyl-5-acetoxy-1,3-oxathiolane (XVI);
cis- and tran-2-ethoxycarbonyl-5-(uracil-1xe2x80x2-yl)-1,3-oxathiolane (XVII);
cis- and trans-2-t-butyldimethylsilyloxy-methyl-5-(uracil-1xe2x80x2-yl)-1,3-oxathiolane (XIX);
cis- and trans-2-t-butyldimethylsilyloxy-methyl-5-(cytosin-1xe2x80x2-yl)-1,3-oxathiolane (XX);
cis- and trans-2-ethoxycarbonyl-5-(methoxycarbonyloxy)-1,3-oxathiolane (XXI);
cis- and trans-2-t-butyldiphenylsilyloxy-methyl-5-(methoxycarbonyloxy)-1,3-oxathiolane (XXII);
cis- and trans-2-t-butyldiphenylsilyloxy-methyl-5-(cytosin-1xe2x80x2-yl)-1,3-oxathiolane (XXIII);
cis- and trans-2-t-butyldiphenylsilyloxy-methyl-5-(N4-acetylcytosin-1xe2x80x2-yl)-1,3-oxathiolane (XXIV);
cis- and trans-2-chloromethyl-4-(m-chloro-benzoyloxy)-1,3-dioxolane (XXVII);
cis- and trans-2-benzoyloxymethyl-1,3-dioxolane-4-carboxylic acid (XXXII);
cis- and trans-2-benzoyloxymethyl-4-(m-chlorobenzoyloxy)-1,3-dioxolane (XXXIII);
2-benzoyloxyacetaldehyde bis (2-methoxyethyl) acetal (XLIV);
2-hydroxyacetaldehyde bis(2-methoxyethyl)acetal (XLV);
cis- and trans-2-benzoyloxymethyl-4-(2-methoxyethoxy)-1,3-dioxolane (XLVI);
cis- and trans-2-benzoyloxymethyl-4-acetyl-1,3-dioxolane (XLVIII); and
cis- and trans-2-benzoyloxymethyl-4-acetoxy-1,3-dioxolane (XLIX).
In addition, the following intermediates, although not specifically depicted in the above identified processes, are important intermediates for making the oxathiolane and dioxolane compounds of this invention:
2-thiobenzoylacetaldehyde bis(2-methoxyethyl) acetal;
2-thioacetaldehyde bis(2-methoxyethyl acetal;
cis- and trans-2-benzoyloxymethyl-5-(2-methoxyethoxy)-1,3-oxathiolane.
cis- and trans-2-hydroxymethyl-5-hydroxy-1,3-oxathiolane; and
cis- and trans-2-acetoxymethyl-5-1,3-oxathiolane.
Many of the reactions described hereinabove have been extensively reported in the context of purine nucleoside synthesis, for example, in xe2x80x9cNucleoside Analoguesxe2x80x94Chemistry, Biology and Medical Applicationsxe2x80x9d, R. T. Walker et al., Eds, Plenum Press, New York (1979) at pages 193-223, the text of which is incorporated by reference herein.
As used in the processes of this invention, a xe2x80x9cleaving groupxe2x80x9d is an atom or group which is displaceable upon reaction with an appropriate base, with or without a Lewis acid. Suitable leaving groups include alkoxy carbonyl groups such as ethoxy carbonyl; halogens such as iodine, bromine, chlorine, or fluorine; amido; azido; isocyanato; substituted or unsubstituted, saturated or unsaturated thiolates, such as thiomethyl or thiophenyl; substituted or unsubstituted, saturated or unsaturated selenino compounds, such as phenyl selenide or alkyl selenide; substituted or unsubstituted, saturated or unsaturated aliphatic or aromatic ketones such as methyl ketone; or xe2x80x94OR where R is a substituted or unsubstituted, saturated or unsaturated alkyl group, e.g., C1-6 alkyl or alkenyl group; a substituted or unsubstituted aliphatic or aromatic acyl group, e.g., a C1-6 aliphatic acyl group such as acetyl and an aromatic acyl group such as benzoyl; a substituted or unsubstituted, saturated or unsaturated alkoxy or aryloxy carbonyl group, such as methyl carbonate and phenyl carbonate; substituted or unsubstituted sulphonyl imidazolide; substituted or unsubstituted aliphatic or aromatic amino carbonyl group, such as phenyl carbamate; substituted or unsubstituted alkyl imidate group such as trichloroacetamidate; substituted or unsubstituted, saturated or unsaturated phosphonates, such as diethylphosphonate: substituted or unsubstituted aliphatic or aromatic sulphonyl group, such as tosylate; or hydrogen.
It will be appreciated that the reactions of the above-described processes may require the use of, or conveniently may be applied to, starting materials having protected functional groups, and deprotection might thus be required as an intermediate or final step to yield the desired compound. Protection and deprotection of functional groups may be effected using conventional means. Thus, for example, amino groups may be protected by a group selected from aralkyl (e.g., benzyl), acyl or aryl (e.g., 2,4-dinitrophenyl); subsequent removal of the protecting group being effected when desired by hydrolysis or hydrogenolysis as appropriate using standard conditions. Hydroxyl groups may be protected using any conventional hydroxyl protecting group, for example, as described in xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d, Ed. J. F. W. McOmie (Plenum Press, 1973) or xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d by Theodora W. Greene (John Wiley and Sons, 1981). Examples of suitable hydroxyl protecting groups include groups selected from alkyl (e.g., methyl, t-butyl or methoxymethyl), aralkyl (e.g., benzyl, diphenylmethyl or triphenylmethyl), heterocyclic groups such as tetrahydropyranyl, acyl, (e.g., acetyl or benzoyl) and silyl groups such as trialkylsilyl (e.g., t-butyldimethylsilyl). The hydroxyl protecting groups may be removed by conventional techniques. Thus, for example, alkyl, silyl, acyl and heterocyclic groups may be removed by solvolysis, e.g., by hydrolysis under acidic or basic conditions. Aralkyl groups such as triphenylmethyl may similarly be removed by solvolysis, e.g., by hydrolysis under acidic conditions. Aralkyl groups such as benzyl may be cleaved, for example, by treatment with BF3/etherate and acetic anhydride followed by removal of acetate groups so formed at an appropriate stage in the synthesis. Silyl groups may also conveniently be removed using a source of fluoride ions such as tetra-n-butylammonium fluoride.
In the above processes the compounds of formula (I) are generally obtained as a mixture of the cis and trans isomers.
These isomers may be separated, for example, by acetylation, e.g., with acetic anhydride followed by separation by physical means, e.g., chromatography on silica gel and deacetylation, e.g., wish methanolic ammonia or by fractional crystallization.
Pharmaceutically acceptable salts of the compounds of the invention may be prepared as described in U.S. Pat. No. 4,383,114, the disclosure of which is incorporated by reference herein. Thus, for example, when it is desired to prepare an acid addition salt of a compound of formula (I), the product of any of the above procedures may be converted into a salt by treatment of the resulting free base with a suitable acid using conventional methods. Pharmaceutically acceptable acid addition salts may be prepared by reacting the free base with an appropriate acid optionally in the presence of a suitable solvent such as an ester (e.g., ethyl acetate) or an alcohol (e.g., methanol, ethanol or isopropanol). Inorganic basic salts may be prepared by reacting the free base with a suitable base such as an alkoxide (e.g., sodium methoxide) optionally in the presence of a solvent such as an alcohol (e.g., methanol). Pharmaceutically acceptable salts may also be prepared from other salts, including other pharmaceutically acceptable salts, of the compounds of formula (I) using conventional methods.
A compound of formula (I) may be converted into a pharmaceutically acceptable phosphate or other ester by reaction with a phosphorylating agent, such as POCl3, or a suitable esterifying agent, such as an acid halide or anhydride, as appropriate. An ester or salt of a compound of formula (I) may be converted to the parent compound, for example, by hydrolysis.
Where the compound of formula (I) is desired as a single isomer it may be obtained either by resolution of the final product or by stereospecific synthesis from isomerically pure starting material or any convenient intermediate.
Resolution of the final product, or an intermediate or starting material therefore may be effected by any suitable method known in the art: see for example, Stereochemistrv of Carbon Compounds, by E. L. Eliel (McGraw Hill, 1962) and Tables of Resolving Agents, by S. H. Wilen. 
The invention will be further described by the following examples which are not intended to limit the invention in any way. All temperatures are in degrees celsius.